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The prognostic value of pre-operative serum tetranectin, CA-125 and a combined index in women with primary ovarian cancer.

OBJECTIVE: To study the prognostic value of pre-operative serum tetranectin (TN), CA125 levels and a mathematical formula (Index1) in primary ovarian cancer. MATERIALS AND METHODS: The study group consisted of sixty-six patients with varying FIGO stages I-IV. The end-point was death from ovarian cancer. Evaluation was by univariate life-tables analyses and the multivariate Cox analysis. In the Cox analyses, the variables were tested respectively in actual values and as dichotomy variables with different cut-off levels: 6.7, 7.3 and 8.2 mg/l for TN, 35, 65, 100 and 165 U/ml for CA125. RESULTS: In stages I+II only CA125 was found to be significantly prognostic, whereas TN was of no prognostic value by univariate statistics. For stages III+IV patients significantly better survivals were found for patients with TN levels above the respective cut-offs compared to patients with low TN levels, whereas no significant value was found for CA125 by univariate statistics. In the Cox analyses, FIGO stage was the strongest and TN the second most prognostic variable, followed by age. CA125, Index1 and tumor types were of no prognostic value. The strongest prognostic value for TN was found at the cut-off level 8.2 mg/l (relative hazard for FIGO stages = 3.3 and for TN = 2.6). CONCLUSION: TN was a strong prognostic variable in patients with advanced ovarian cancer. To the contrary, CA125 was a strong prognostic factor in patients with a localised ovarian cancer and of no prognostic value in patients with advanced cancer. The variables may be useful in the selection of patients with a poor outcome for new treatment strategies.

Adult↗

Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease.

UNLABELLED: The aim of the present study is to compare brain atrophy with hypometabolism as preclinical markers of Alzheimer's disease (AD) by studying presymptomatic individuals from families with known early-onset autosomal dominant AD (FAD) carrying mutations in the Presenilin 1 gene. METHODS: Seven asymptomatic at-risk FAD individuals (age, 35-49 y; 4 women; education >/= 12 y) and 7 matched healthy control subjects received complete clinical, neuropsychologic, MRI, and (18)F-FDG PET examinations. Regions of interest (ROIs: whole brain [WB], hippocampus [Hip], entorhinal cortex [EC], posterior cingulate cortex [PCC], inferior parietal lobule [IPL], and superior temporal gyrus (STG]) were drawn on the MRI scans of all subjects and used to measure volumes on MRI and glucose metabolism (MRglc) from the MRI-coregistered, atrophy-corrected PET scans. RESULTS: Compared with controls and after correcting for head size, MRI volume reductions in FAD subjects were restricted to the IPL (18%, P < 0.02). After atrophy correction and adjusting for pons MRglc, PET MRglc reductions were found in all FAD subjects compared with controls in the WB (13%), bilaterally in the IPL (17%) and in the STG (12%), and in the left EC (21%), PCC (20%), and Hip (12%) (P values < 0.05). PET MRglc measurements were consistently less variable than MRI measures, yielding significantly larger effect sizes in separating FAD from controls. CONCLUSION: Presymptomatic FAD individuals show widespread MRglc reductions consistent with the typical AD PET pattern in the relative absence of structural brain atrophy. These data further suggest that PET MRglc measures may serve as biomarkers for the preclinical diagnosis of AD.

Adult↗

Serum albumin level on admission as a predictor of death, length of stay, and readmission.

We studied the serum albumin level within 48 hours of hospitalization for acute illness to predict in-hospital death, length of stay, and readmission in 15,511 patients older than 40 years. Patients with low serum albumin levels (less than 34 g/L), who made up 21% of the population, were more likely to die, had longer hospital stays, and were readmitted sooner and more frequently than patients with normal albumin levels. The in-hospital mortality was 14% among patients with low albumin levels, as compared with 4% among patients with normal levels. Although the serum albumin level was a nonspecific marker, it was a stronger predictor of death, length of stay, and readmission than age. We conclude that the serum albumin level on admission is an important variable that should be incorporated in severity-of-illness measures based on physiologic indexes.

Adult↗

Inter-observer variation of p53 immunohistochemistry--an assessment of a practical problem and comparison with other studies.

The aims of this study were to analyse the expression of p53 by immunohistochemistry in a range of malignant and pre-malignant conditions and to assess the degree of inter-observer variability in interpretation of p53 immunostaining. Formalin-fixed paraffin-embedded sections from 28 colorectal carcinomas (CRC), 40 cervical intraepithelial neoplasia lesions (CIN), 22 transitional cell carcinomas of the bladder (TCC), 10 invasive squamous carcinomas of uterine cervix and 21 squamous cell carcinomas of skin were examined. A polyclonal antibody was used in 90 cases. A monoclonal antibody was used in the remainder. Ten cases were stained with both. Aberrant expression of p53 protein was documented in 48% of squamous cell carcinomas of skin, 29% of CRC, 22% of CIN and 23% of TCC. All cases of squamous cell carcinoma of uterine cervix were negative. Inter-observer variation occurred in 7% of cases examined. This was confined to two tumour groups, TCC and CIN. Our results showed that p53 oncoprotein expression by immunohistochemistry was identified in 26% of cases but the range was wide (0-48%) and appeared to be tumour specific. Inter-observer variability in the interpretation of immunohistochemical staining was low (7%) and was restricted to two tumour groups.

Biomarkers, Tumor↗

Evaluation of the catabolic activity of cartilage by measurement of serum keratan sulfate concentration in foals.

OBJECTIVES: To determine keratan sulfate (KS) concentration in the serum of foals at the early stage of growing, and to evaluate the role of serum KS as a cartilage catabolic marker, comparing its values with the fluctuation of serum alkaline phosphatase (ALP) activity as a measurement of osteoblastic activity. ANIMALS: 12 foals with normal growth and 3 foals with joint abnormalities within 18 months after birth. PROCEDURE: Measurement of KS concentration and ALP activity in serum and radiographic and physical examinations were done. RESULTS: In all foals, serum KS concentration was high from 1 week after birth to 3 months of age, while serum ALP decreased with aging. The value started to decrease rapidly from 3 to 5 months of age, then gradually reached adult values. During the first 3 months, KS concentration in male foals was significantly higher than that in female foals. In 3 foals which had joint problems, KS concentration was higher than that in normally growing foals at 1 week, and at 1, 2, and 3 months of age. CONCLUSIONS: Cartilage catabolic activity is higher in developing foals up to 3 months of age, suggesting that the immature joint at this time could be easily affected by any factor of loading. Moreover, though only 3 diseased foals were examined, higher serum KS concentration in these foals suggest that this variable might be a useful measure of joint diseases, even at an early stage of life in foals.

Aging↗

Diagnostic value of antibodies to filaggrin in rheumatoid arthritis.

OBJECTIVE: To determine the prevalence of antibodies to filaggrin in a cross sectional sample of patients with rheumatoid arthritis (RA). METHODS: Filaggrin from human skin was either extracted with 0.05% Nonidet P-40 and then partially purified by precipitating in ethanol and resuspending in water (Nonidet preparation) or extracted with 9 M urea and then purified by sequential fractionation on a DEAE Sephadex column and on a strong cation exchange column (purified preparation). Antibodies to filaggrin were detected using immunoblotting techniques with sera diluted 1:50. Antikeratin antibodies (AKA) were detected using indirect immunofluorescence microscopy on sections of rat esophagus. RESULTS: Antibodies to filaggrin were detected in 5 of 30 sera of patients with RA using filaggrin from the Nonidet preparation and 6 of 49 sera using filaggrin from the purified preparation. AKA were detected in 13 of 40 sera. A positive correlation existed between the presence of AKA and the presence of antibodies to filaggrin using the purified preparation (p=0.017). CONCLUSION: These data indicate that the reactivity of RA sera with filaggrin is not identical to the presence of AKA and is variable depending upon the preparation of filaggrin used. The diagnostic value of antibodies to filaggrin remains to be proven.

Animals↗

Comprehensive label-free method for the relative quantification of proteins from biological samples.

Pharmaceutical companies and regulatory agencies are broadly pursuing biomarkers as a means to increase the productivity of drug development. Quantifying differential levels of proteins from complex biological samples such as plasma or cerebrospinal fluid is one specific approach being used to identify markers of drug action, efficacy, toxicity, etc. We have developed a comprehensive, fully automated, and label-free approach to relative protein quantification from LC-MS/MS experiments of proteolytic protein digests including: de-noising, mass and charge state estimation, chromatographic alignment, and peptide quantification via integration of extracted ion chromatograms. Results from a variance components study of the entire method indicate that most of the variability is attributable to the LC-MS injection, with a median peptide LC-MS injection coefficient of variation of 8% on a ThermoFinnigan LTQ mass spectrometer. Spiked recovery results suggest a quantifiable range of approximately 32-fold for a sample protein.

Amino Acid Sequence↗

Hypoxaemia in sickle cell disease: biomarker modulation and relevance to pathophysiology.

BACKGROUND: Nocturnal oxyhaemoglobin desaturation might have a role in CNS complications related to sickle cell disease, and rates of painful crises. We attempted to examine the biological relations, and describe the haematological risk factors for oxyhaemoglobin desaturation. METHODS: The study population included children with sickle cell disease and controls. Cellular activation was assessed by measurement of soluble vascular cell adhesion molecule 1, P-selectin, L-selectin, and leukotriene B4. Erythrocyte-endothelial adhesion and routine haematological variables were assessed. Oxygen saturation (SaO2) was measured by pulse oximetry while children were awake and asleep. Children with a mean sleeping SaO2 of < or =93% were identified as hypoxaemic. Children were divided into four groups: controls (ten children), HbSC (nine, all normoxic), HbSS normoxic (13), and HbSS hypoxaemic (15). FINDINGS: Among haematological variables, sleeping SaO2 correlated only with packed-cell volume (r=0.7; p<0.0001). Inverse relations were noted between sleeping SaO2 and adhesion (-0.45; p<0.01), and markers of white-cell (-0.51; p<0.01), platelet (-0.61; p<0.001), and endothelial activation (-0.46; p<0.01). In the HbSS group who had sleeping hypoxaemia, waking SaO2 measurements showed continuing hypoxaemia, with similar correlation between SaO2 and cell activation markers. INTERPRETATION: Our adhesion-related findings suggest a potential mechanism for the increased occurrence of clinical vaso-occlusive crises in individuals with sickle cell disease who have oxyhaemoglobin desaturation. Release of cellular mediators in hypoxaemia, and the relation between anaemia and oxyhaemoglobin desaturation, suggest that risk factors for stroke, including anaemia, might have a role in CNS-vasculopathy through hypoxia-mediated pathways. Further more, hypoxaemia in the older child also occurs during the day; such mild untreated hypoxia could lead to an increased risk of vaso-occlusive episodes.

Adolescent↗

Biomarkers predictive of lymph node metastases in oral squamous cell carcinoma.

PURPOSE: The ability of oral squamous cell carcinoma to metastasize to lymph nodes does not always show a relationship with clinical staging. The aim of this study was to attempt to define a trend for predictive histopathologic and/or molecular biomarkers in the development of nodal metastasis by analyzing 2 clinically extreme groups. PATIENTS AND METHODS: Patients with small primary tumors (T1, T2) with lymph node metastasis and patients with large primary tumors (T3, T4) without metastatic disease were identified among 315 consecutive cases of primary oral squamous cell carcinoma. Group comparisons were made with use of a Mann-Whitney test, and associations among the variables were assessed with nonparametric and parametric correlational analyses. RESULTS: The degree of keratinization was significantly less in primary tumors with lymph node metastasis (P < or = .01). The degree of keratinization was significantly associated with nuclear pleomorphism (P =.02), number of mitoses (P =.02), stage of invasion (P =.002), and p53 expression (P =.04), independent of clinical stage of the tumor. Other microscopic features and immunohistochemical markers did not differ significantly between the groups (P >.05). CONCLUSION: These data indicate that there still is no single predictive parameter superior to the degree of keratinization to identify patients at risk for the development of regional metastasis.

Adult↗

The effect of statin therapy on lipoprotein associated phospholipase A2 levels.

Lipoprotein associated phospholipase A2 (Lp-PLA2), a biomarker of oxidation and inflammation, has been associated with increased coronary heart disease (CHD) risk. To date, data examining the effect of HMG CoA reductase inhibitors on Lp-PLA2 are few. We evaluated the effect of pravastatin 40 mg daily versus placebo on Lp-PLA2 levels among 481 subjects free of cardiovascular disease (pravastatin N=246 and placebo N=235) who participated in the Pravastatin Inflammation/CRP Study (PRINCE). After 12 weeks, Lp-PLA2 levels decreased by 22.1% among pravastatin treated participants and by 7.8% among those randomized to placebo (p<0.001). These results were similar in all subgroups evaluated according to age, blood pressure, lipid parameters, diabetic status, smoking status, aspirin use, body mass index and gender. There were correlations between change in Lp-PLA2 levels and baseline Lp-PLA2 levels (r=-0.63, p<0.001), total cholesterol change (r=-0.26, p<0.001), LDL-C change (r=-0.32, p<0.001) and C-reactive protein (CRP) change (r=-0.13, p=0.05). Multivariate linear regression models that assessed the relationship between the log difference in Lp-PLA2 at 12 weeks and treatment revealed a beta-coefficient of 0.15 for the treatment variable (p<0.01). However, adjustment for change in LDL-C substantially attenuated the beta-coefficient associated with treatment to 0.07 (P<0.005) and after additional control for other potential confounders, the effect of treatment was no longer significant. Thus, Lp-PLA2 levels were significantly reduced at 12 weeks by pravastatin, an effect that was significantly related to LDL cholesterol reduction accounting for about 6% of the variability in this response. Moreover, pravastatin induced reduction in Lp-PLA2 was no longer significant after taking the latter into account.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

Dietary conjugated linoleic acid (CLA) induces apoptosis of colonic mucosa in 1,2-dimethylhydrazine-treated rats: a possible mechanism of the anticarcinogenic effect by CLA.

One of the objectives of the present study was to investigate whether 1 % conjugated linoleic acid (CLA) in the diet reduced tumour incidence in the colon of 1,2-dimethylhydrazine (DMH)-treated rats. Colon cancer was induced by injecting 6-week-old, male, Sprague-Dawley rats with 15 mg/kg DMH twice per week for 6 weeks. They were fed either 1 % CLA or a control diet ad libitum for 30 weeks. Dietary CLA significantly decreased colon tumour incidence (P<0.05). Our second objective was to investigate whether apoptosis in the colon mucosa of DMH-treated rats was affected by the amount of dietary CLA and whether the changes in apoptosis were related to those in fatty acid-responsive biomarkers. For this purpose, rats were killed after being fed a diet containing 0 %, 0.5 %, 1 % or 1.5 % CLA for 14 weeks. CLA was undetected in the mucosa of rats fed the 0 % CLA diet and increased to 5.9 mg/g phospholipid in rats fed the 0.5 % diet. The apoptotic index estimated by the terminal deoxynucleotidyl transferase-mediated dUTP nick and labelling technique was increased by 251 % and the 1,2-diacylglycerol content was decreased by 57 % in rats fed 0.5 % CLA. No further changes in these variables were observed when CLA in the diet was raised to 1.0 % or 1.5 %. However, dietary CLA decreased mucosal levels of prostaglandin E2, thromboxane B2 and arachidonic acid in a dose-dependent manner. The present data indicate that dietary CLA can inhibit DMH-induced colon carcinogenesis by mechanisms probably involving increased apoptosis.

1,2-Dimethylhydrazine↗

Molecular approaches to evaluate pollutants.

Many organisms are in use to test pollutants and their extensive variability clearly emerges from reviews since researchers in the world are involved in continuous effort to set up new assays and to improve those already in use. In the present paper we focus the attention on the mixed function oxidase system and the DNA adduct formation which are two biomarkers widely used and extensively studied in mammals and fish by different Authors. We compare their results with the ones we obtained in amphibians, which result to be a good model. Moreover we present some significative results obtained by the use of cultured cell lines to test the herbicide MCPA. The results obtained demonstrate that the amphibian Xenopus is a suitable indicator for induction of cytochrome P-450 by B[a]P as well as for production of DNA adducts. Cultured cells evidenced that cytoskeletal array and thiol proteins are molecular targets of the herbicide used, demonstrating that risk assessment can be properly analysed in in vitro systems.

2-Methyl-4-chlorophenoxyacetic Acid↗

Superficial (early) endocervical adenocarcinoma in situ: a study of 12 cases and comparison to conventional AIS.

Although established histologic criteria for the diagnosis of endocervical adenocarcinoma in situ (AIS) have been published, some lesions are not readily classified or present with more subtle degrees of epithelial atypia. Lesions confined to the surface mucosa may be particularly challenging, possibly because they represent early disease. Twelve cases of superficial AIS (SAIS) confined to the surface mucosa or crypt openings culled from the in-house and consultation practices were examined histologically, immunostained for MIB-1 and p16, and analyzed (when possible) for HPV nucleic acids by DNA-DNA in situ hybridization (INFORM). The mean age was 26.7 years for SAIS versus 37.0 years for 42 consecutive cases of conventional AIS from the same practice (P < 0.001). Seven and five were biopsies and conization specimens, respectively. Five coexisted with CIN, four arose in endocervical papillae, and two arose in endocervical polyps. Nuclear hyperchromasia was conspicuous in 10 and mitoses were present in all; however, apoptosis was rare or absent in four, and six exhibited only mild nuclear atypia. Mib-1 staining exceeded 40% in 5 of 7 cases tested, and all (8 of 8) were strongly positive for p16(ink4). Five of five were positive for HPV by ISH with an "integrated" dot-like pattern. SAIS is an early variant of AIS that 1) occurs at a younger mean age, 2) exhibits variable atypia, and 3) arises adjacent to morphologically normal columnar epithelium. Diffuse p16 expression and integrated HPV pattern are identical to that seen in more extensive forms of the disease. Superficial AIS should be suspected in endocervical columnar epithelium with segmental nuclear hyperchromasia with mitotic activity, and confirmed by biomarker staining (p16 and Mib-1) if the pathologist is uncertain of the diagnosis.

Adenocarcinoma↗

Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography.

PURPOSE: Variable uptake of the glucose analog (18)fluorodeoxyglucose (FDG) has been noticed in positron emission tomography (PET) studies of breast cancer patients, with low uptake occurring especially in lobular cancer. At present, no satisfactory biologic explanation exists for this phenomenon. This study compared (18)FDG uptake in vivo with biomarkers expected to be involved in the underlying biologic mechanisms. PATIENTS AND METHODS: Preoperative (18)FDG-PET scans were performed in 55 patients. (18)FDG activity was assessed visually by three observers using a four-point score. Tumor sections were stained by immunohistochemistry for glucose transporter-1 (Glut-1); Hexokinase (HK) I, II, and III; macrophages; hypoxia-inducible factor-1-alfa (HIF-1alpha); vascular endothelial growth factor (VEGF(165)); and microvessels. Mitotic activity index (MAI), amount of necrosis, number of lymphocytes, and tumor cells/volume were assessed. RESULTS: There were positive correlations between (18)FDG uptake and Glut-1 expression (P <.001), MAI (P =.001), amount of necrosis (P =.010), number of tumor cells/volume (P =.009), expression of HK I (P =.019), number of lymphocytes (P =.032), and microvessel density (r =.373; P =.005). HIF-1alpha, VEGF(165), HK II, HK III, and macrophages showed no univariate correlation with (18)FDG. In logistic regression, however, HIF-1alpha and HK II added value to MAI and Glut-1. CONCLUSION: (18)FDG uptake in breast cancer is a function of microvasculature for delivering nutrients, Glut-1 for transportation of (18)FDG into the cell, HK for entering (18)FDG into glycolysis, number of tumor cells/volume, proliferation rate (also reflected in necrosis), number of lymphocytes (not macrophages), and HIF-1alpha for upregulating Glut-1. Together, these features explain why breast cancers vary in (18)FDG uptake and elucidate the low uptake in lobular breast cancer.

Adult↗

Study design and data analysis in clinical and environmental models of nephrotoxicity.

Protocols for clinical studies of nephrotoxicity may include several elements. They include background information, study objectives, study design, data handling and analysis, organization and administration, and methods and definitions. Response variables used to indicate the development of clinically apparent renal disease should be clearly defined. Susceptibility factors such as diabetes, hypertension, cardiovascular disease, obesity, smoking history, and genetic factors may influence the development of renal disease and other health outcomes. These factors may also affect the pattern of abnormal biomarkers that appear during the development of renal disease. Some individuals who are normal by standard clinical criteria will be in various stages of disease development and will have abnormal biomarker levels. With all approaches, an adequate baseline assessment of biomarker values is critically important. Consistent findings among studies reinforce conclusions.

Biomarkers↗

Multimodal deep learning for immunotherapy response prediction and biomarker discovery in non-small cell lung cancer.

OBJECTIVE: Immunotherapy has emerged as a promising treatment for advanced non-small cell lung cancer (NSCLC), but accurately predicting which patients will benefit from it remains a major clinical challenge. To address this, we aim to develop a novel multimodal method, DeepAFM, that integrates histopathology, genomic features, and clinical information to predict patient responses to anti-PD-(L)1 immunotherapy. MATERIALS AND METHODS: A total of 93 patients with advanced NSCLC were included in this study. Histopathological whole-slide images were processed using a self-supervised VQVAE2 for representation learning. PCA and K-means clustering were then applied for dimensionality reduction and feature grouping. Key regions of interest were visualized through permutation importance evaluation and color-coding techniques. The extracted histopathological features, along with genomic alterations and clinical variables, were integrated into the DeepAFM multimodal prediction model. RESULTS: The DeepAFM achieved a high predictive performance with an area under the curve (AUC) of 0.77 (95% confidence interval: 0.69-1.00). Attention-based heatmaps revealed that the model could identify critical pathological patterns, genomic mutations, and clinical indicators associated with patient responses to immunotherapy. DISCUSSION: The integration of multimodal data enabled the model to capture complex interactions among pathology, genomics, and clinical characteristics, enhancing the interpretability and predictive power of immunotherapy response prediction. The visualization techniques facilitated the identification of biologically meaningful features and potential biomarkers. CONCLUSION: This study demonstrates the effectiveness of the DeepAFM in predicting responses to immunotherapy in advanced NSCLC. The approach not only improves prediction accuracy but also provides valuable insights for personalized treatment strategies and biomarker discovery.

Humans↗

Nuclear morphometry and molecular biomarkers of actinic keratosis, sun-damaged, and nonexposed skin.

Computer-assisted image analysis is useful for quantifying the histologic and molecular changes of sun-induced squamous cell carcinoma progression. We used the CAS 200 image analysis system to measure nuclear morphometric parameters, p53 expression, and proliferation markers in actinic keratosis (AK), sun-exposed, and normal skin in 51 patients. Nuclear morphometry revealed significant increases in nuclear absorbance, irregularity of nuclear shape, and nuclear size in AK compared with normal and sun-damaged skin. These parameters showed significantly greater variability in AK nuclei. Argyrophyllic nucleolar organizer area and number were also significantly greater in AK compared with sun-damaged skin and normal skin. Ki67 and p53 expressions were both increased in sun-damaged skin relative to normal and greater still in AK. These data are evidence that sun damage induces proliferation and p53 abnormalities before the appearance of nuclear abnormalities and their associated DNA instability. Following these changes during a skin cancer chemopreventative trial can then help assess the efficacy of the agent and help determine where in the progression of neoplastic changes it exerts its biological effects.

Adult↗

Expression analysis of the human kallikrein 7 (KLK7) in breast tumors: a new potential biomarker for prognosis of breast carcinoma.

Kallikreins are a subgroup of serine proteases that are involved in the post-translational processing of polypeptide precursors. Growing evidence suggests that many kallikreins are implicated in carcinogenesis. Human kallikrein gene 7 (KLK7; HSCCE) is a new member of the human kallikrein gene family. KLK7 is expressed in normal breast tissue and is up-regulated in breast cancer cells by estrogens and glucocorticoids. In the present study, expression of the KLK7 gene in 92 breast cancer tissues was analyzed by reverse transcription-PCR (RT-PCR) and direct sequencing of several samples. The results were correlated with other clinicopathological variables and patient outcome. KLK7 gene expression was significantly lower in breast cancer patients of low stage (I/II) (p = 0.011) and patients with positive progesterone receptors (p = 0.022). Survival analysis showed that breast cancer patients with KLK7 positive tumors have relatively shorter disease-free survival (DFS) and overall survival (OS) than patients with KLK7 negative tumors. These data suggest that KLK7 gene expression may be used as a marker of unfavorable prognosis for breast cancer patients.

Adult↗